Sporanox

Sporanox 100 mg Capsules.

Each capsule contains itraconazole 100 mg.

For excipients, see 6.1.

Capsules, hard

Capsule (Size 0): opaque blue cap and pink transparent body containing coated beads.

1. Vulvovaginal candidosis.

2. Pityriasis versicolor.

3. Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum.

4. Oropharyngeal candidosis.

5. Onychomycosis caused by dermatophytes and/or yeasts.

6. The treatment of histoplasmosis.

7. Sporanox is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity.

Sporanox is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.

Sporanox is for oral administration and must be taken immediately after a meal for maximal absorption. The capsules must be swallowed whole.

Treatment schedules in adults for each indication are as follows:

For skin, vulvovaginal and oropharyngeal infections, optimal clinical and mycological effects are reached 1 - 4 weeks after cessation of treatment and for nail infections, 6 - 9 months after the cessation of treatment. This is because elimination of itraconazole from skin, nails and mucous membranes is slower than from plasma.

The length of treatment for systemic fungal infections should be dictated by the mycological and clinical response to therapy:

¹ The duration of treatment should be adjusted depending on the clinical response.

Impaired absorption in AIDS and neutropenic patients may lead to low itraconazole blood levels and lack of efficacy. In such cases, blood level monitoring and if necessary, an increase in itraconazole dose to 200 mg twice daily, is indicated.

Special populations

Paediatrics

Clinical data on the use of Sporanox Capsules in paediatric patients are limited.Special warnings and precautions for use.

Elderly

Clinical data on the use of Sporanox Capsules in elderly patients are limited.Special warnings and precautions for use.

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

Hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment.Pharmacokinetic properties - Special Populations, Hepatic impairment)

- Women of childbearing potential taking Sporanox Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Sporanox Capsules therapy.

Elderly

Clinical data on the use of Sporanox Capsules in elderly patients are limited.Special warnings and precautions for use.

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

Hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment.Pharmacokinetic properties - Special Populations, Hepatic impairment)

- Women of childbearing potential taking Sporanox Capsules should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Sporanox Capsules therapy.

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing Sporanox Capsules to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Sporanox^® IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion.Interaction with other medicinal products and other forms of interaction) due to an increased risk of congestive heart failure.

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Sporanox Capsules.Pharmacokinetic properties - Special Populations, Hepatic impairment.)

Reduced gastric acidity

Absorption of itraconazole from Sporanox Capsules is impaired when gastric acidity is reduced. Interaction with other medicinal products and other forms of interaction.

Paediatrics

Clinical data on the use of Sporanox Capsules in paediatric patients is limited. The use of Sporanox Capsules in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.

Elderly

Clinical data on the use of Sporanox Capsules in elderly patients are limited. It is advised to use Sporanox Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Interaction with other medicinal products and other forms of interaction). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Immunocompromised patients

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Sporanox Capsules may be decreased.

Patients with immediately life-threatening systemic fungal infections

Patients with AIDS

In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Neuropathy

If neuropathy occurs which may be attributable to Sporanox Capsules, the treatment should be discontinued.

Disorders of Carbohydrate Metabolism

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of Sporanox therapy.

Interchangeability

It is not recommended that Sporanox Capsules and Sporanox Oral Solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.

Interaction Potential

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.Interaction with other medicinal products and other forms of interaction.

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Sporanox Capsules.Pharmacokinetic properties - Special Populations, Hepatic impairment.)

Reduced gastric acidity

Absorption of itraconazole from Sporanox Capsules is impaired when gastric acidity is reduced. Interaction with other medicinal products and other forms of interaction.

Paediatrics

Clinical data on the use of Sporanox Capsules in paediatric patients is limited. The use of Sporanox Capsules in paediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.

Elderly

Clinical data on the use of Sporanox Capsules in elderly patients are limited. It is advised to use Sporanox Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Interaction with other medicinal products and other forms of interaction). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Immunocompromised patients

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of Sporanox Capsules may be decreased.

Patients with immediately life-threatening systemic fungal infections

Patients with AIDS

In patients with AIDS having received treatment for a systemic fungal infection such as sporotrichosis, blastomycosis, histoplasmosis or cryptococcosis (meningeal or non-meningeal) and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.

Neuropathy

If neuropathy occurs which may be attributable to Sporanox Capsules, the treatment should be discontinued.

Disorders of Carbohydrate Metabolism

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of Sporanox therapy.

Interchangeability

It is not recommended that Sporanox Capsules and Sporanox Oral Solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.

Interaction Potential

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.Interaction with other medicinal products and other forms of interaction.

Itraconazole is mainly metabolised through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.

Drugs that may decrease itraconazole plasma concentrations

Drugs that reduce the gastric acidity (e.g. acid neutralising medicines such as aluminum hydroxide, or acid secretion suppressors such as H₂-receptor antagonists and proton pump inhibitors) impair the absorption of itraconazole from itraconazole capsules. It is recommended that these drugs be used with caution when coadministered with itraconazole capsules:

It is recommended that itraconazole be administered with an acidic beverage (such as non-diet cola) upon co-treatment with drugs reducing gastric acidity.

It is recommended that acid neutralising medicines (e.g. aluminum hydroxide) be administered at least 1 hour before or 2 hours after the intake of Sporanox Capsules.

Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.

Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be largely reduced. Examples include:

Antibacterials: isoniazid, rifabutin (see also under Drugs that may have their plasma concentrations increased by itraconazole), rifampicin.

Anticonvulsants: carbamazepine, (see also under Drugs that may have their plasma concentrations increased by itraconazole), phenobarbital, phenytoin.

Antivirals: efavirenz, nevirapine.

Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.

Drugs that may increase itraconazole plasma concentrations

Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:

Antibacterials: ciprofloxacin, clarithromycin, erythromycin,

Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under Drugs that may have their plasma concentrations increased by itraconazole), ritonavir (see also under Drugs that may have their plasma concentrations increased by itraconazole),

It is recommended that these drugs be used with caution when coadministered with itraconazole capsules. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma concentrations be measured.

Drugs that may have their plasma concentrations increased by itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolised by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolised drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.

The interacting drugs are categorized as follows:

- 'Contraindicated': Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.

- 'Not recommended': It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

- 'Use with caution': Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured.

Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:

Drugs that may have their plasma concentrations decreased by itraconazole

Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentrations of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adapted if necessary.

Paediatric Population

Interaction studies have only been performed in adults.

Pregnancy

Sporanox Capsules must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus.

In animal studies itraconazole has shown reproduction toxicity.

There is limited information on the use of Sporanox during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with Sporanox has not been established.

Epidemiological data on exposure to Sporanox during the first trimester of pregnancy-mostly in patients receiving short-term treatment for vulvovaginal candidosis-did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.

Women of child bearing potential

Women of childbearing potential taking Sporanox capsules should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Sporanox therapy.

Lactation

A very small amount of itraconazole is excreted in human milk. The expected benefits of Sporanox therapy should be weighed against the risks of breast feeding. In case of doubt, the patient should not breast feed.

No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss , which may occur in some instances, must be taken into account.

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) with Sporanox Capsules treatment identified from clinical trials and/or from spontaneous reporting were headache, abdominal pain, and nausea.Special warnings and precautions for use for additional information on other serious effects.

Tabulated list of adverse reactions

The ADRs in the table below were derived from open-label and double-blind clinical trials with Sporanox Capsules involving 8499 patients in the treatment of dermatomycoses or onychomycosis, and from spontaneous reporting.

The table below presents ADRs by System Organ Class. Within each System Organ Class, the ADRs are presented by incidence, using the following convention:

Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (> 1/10,000 to < 1/1,000); Very rare (< 1/10,000).

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Description of selected adverse reactions

The following is a list of ADRs associated with itraconazole that have been reported in clinical trials of Sporanox Oral Solution and Sporanox I.V., excluding the ADR term “Injection site inflammation”, which is specific to the injection route of administration.

Blood and lymphatic system disorders: Granulocytopenia, Thrombocytopenia

Immune system disorders: Anaphylactoid reaction

Metabolism and nutrition disorders: Hyperglycaemia, Hyperkalaemia, Hypokalaemia, Hypomagnesaemia

Psychiatric disorders: Confusional state

Nervous system disorders: Peripheral neuropathy*, Dizziness, Somnolence, Tremor

Cardiac disorders: Cardiac failure, Left ventricular failure, Tachycardia

Vascular disorders: Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders: Pulmonary oedema, Dysphonia, Cough

Gastrointestinal disorders: Gastrointestinal disorder

Hepatobiliary disorders: Hepatic failure*, Hepatitis, Jaundice

Skin and subcutaneous tissue disorders: Rash erythematous, Hyperhidrosis

Musculoskeletal and connective tissue disorders: Myalgia, Arthralgia

Renal and urinary disorders: Renal impairment, Urinary incontinence

General disorders and administration site conditions: Generalised oedema, Face oedema, Chest pain, Pyrexia, Pain, Fatigue, Chills

Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal

Paediatric population

The safety of Sporanox Capsules was evaluated in 165 paediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo controlled trials; 9 open-label trials; and 1 trial had an open-label phase followed by a double-blind phase). These patients received at least one dose of Sporanox Capsules for the treatment of fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the commonly reported adverse drug reactions (ADRs) in paediatric patients were Headache (3.0%), Vomiting (3.0%), Abdominal pain (2.4%), Diarrhoea (2.4%), Hepatic function abnormal (1.2%), Hypotension (1.2%), Nausea (1.2%), and Urticaria (1.2%). In general, the nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the paediatric patients.

Symptoms and signs

Treatment

In the event of overdosage, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

Pharmacotherapeutic classification: (Antimycotics for systemic use, triazole derivatives).

ATC code: J02A C02

Itraconazole, a triazole derivative, has a broad spectrum of activity.

In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.

For itraconazole, breakpoints have only been established for Candida spp. from superficial mycotic infections (CLSI M27-A2, breakpoints have not been established for EUCAST methodology). The CLSI breakpoints are as follows: susceptible ≤0.125; susceptible, dose-dependent 0.25-0.5 and resistant > 1μg/mL. Interpretive breakpoints have not been established for the filamentous fungi.

In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤ 1 µg/ml. These include:

dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. tropicalis, C. parapsilosis and C. krusei, Cryptococcus neoformans, Malassezia spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., including H. capsulatum; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidiodes immitis; Pseudallescheria boydii; Penicillium marneffei; and various other yeasts and fungi.

Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.

The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp.

Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

General pharmacokinetic characteristics

Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with C_max values of 0.5 µg/ml, 1.1 µg/ml and 2.0 µg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Absorption

Distribution

Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.

Metabolism

Itraconazole is extensively metabolised by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to Itraconazole; trough plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole.

Excretion

Itraconazole is excreted mainly as inactive metabolites in urine (35%) and faeces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose.Based on an oral radiolabelled dose, faecal excretion of unchanged drug varies between 3 - 18% of the dose.

Special Populations

Paediatrics:

Limited pharmacokinetic data are available on the use of itraconazole in the paediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, C_max and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.

Nonclinical data on itraconazole revealed no indications for gene toxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed.

Sugar spheres

Hypromellose 2910 5mPa.s

Macrogol 20000

Capsule shell:

Titanium dioxide

Indigo carmine

Gelatin

Erythrosine

Not applicable.

3 years

Do not store above 30°C.

Store in the original container.

Perlalux tristar blister - plastic foil consisting of 3 layers

* Polyvinylchloride on the outside;

* Low density polyethylene in the middle;

* Polyvinylidene chloride on the inside;

Aluminium foil (thickness 20 μm) coated on the inner side with colourless heat-seal Lacquer: PVC mixed polymers with acrylates, 6 g/m².

or:

PVC blister consisting of -

Polyvinylchloride 'genotherm' glass clear, thickness 250 μm;

Aluminium foil (thickness 20μm) coated on the inner side with a colourless heat-seal Lacquer: PVC mixed polymers with acrylates, 6g/m².

Pack sizes: 4, 6*not marketed, 15, 60 capsules.

No special requirements.

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

00242/0142

18/01/89, 11/01/95

16 April 2013